Cyclophosphamide and especially high-dose cyclophosphamide (for example, 50 mg/kg/day×4 days) has been used for the treatment of certain autoimmune diseases such as, for example, severe aplastic anemia. Low to intermediate doses of cyclophosphamide have also been used in combination chemotherapy for treating certain cancers and appears to work either by stopping the growth of cancer cells or by killing the cancer cells. However, usually remaining cancer cells, especially cancer stem cells, are able to divide, thereby leading to a relapse of the cancer.
More recently, immune-based therapeutics, for example, monoclonal antibodies targeted selectively to tumor specific antigens have been developed for treatment of various types of cancers. However, immune tolerance appears to be the major barrier to the effectiveness of most immune-based therapeutics. It has been reported that immune tolerance results largely from the integration of multiple regulatory mechanisms that have evolved to prevent the development of immunity to tumor specific antigens, which are perceived as self antigens instead of foreign antigens.
Therefore, there is a need to identify therapies or agents which may be used to break immune tolerance which severely limits the use of immune-based therapeutics in the treatment of cancer.